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Immunogenic Cell Death Role in Urothelial Cancer Therapy: History
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Please note this is an old version of this entry, which may differ significantly from the current revision.
Contributor:
Reza Yadollahvandmiandoab
,
Mehrsa Jalalizadeh
,
Keini Buosi
, Herney Andrés Garcia-Perdomo , Leonardo Oliveira Reis

Bladder cancer is the 13th most common cause of cancer death with the highest lifetime cost for treatment of all cancers. The role of a novel therapeutic approach called immunogenic cell death (ICD) in urothelial cancer of the bladder is clarified.

  • bladder cancer
  • immunogenic cell death
  • immunotherapy
  • immune checkpoint inhibitors

1. Introduction

According to estimates, about one million cells die every second in the human body because of normal tissue turnover, and throughout this process the immune system is frequently exposed to dead cells, as well as during damage and infection [1][2]. Physiological mechanisms must be able to distinguish between various types of cell death to effectively eradicate pathogens, promote healing, and prevent autoimmunity. The immune system decides whether the cell death is immunogenic or tolerogenic.
Tolerogenic cell death occurs in the absence of pathogens and does not cause any immune response. Conversely, immunogenic cell death (ICD) is defined as a kind of cell death that triggers an immune response to dead-cell antigens, especially when those antigens come from cancer cells [2]. According to the ICD concept, many kinds of anti-cancer treatments, such as gamma-irradiation, chemotherapeutics, immunotherapy, and photodynamic therapy [3][4][5] provoke immunogenic cell death, most commonly apoptotic cell death. These apoptotic cells present certain danger-associated molecular patterns (DAMPs), including translocation of calreticulin (CRT) to the plasma membrane, secretion of adenosine triphosphate (ATP) from the cytosol into the extracellular space, translocation of HSP70/HSP90 to the cell surface, and release of high mobility group box 1 (HMGB1) from nucleus into the extracellular space [6][7]. These DAMPs are considered as essential hallmarks for cell death to be considered as ICD, and the absence of any one of them reduces the immunogenicity in cell death [8][9][10]. DAMPs mainly cause dendritic cells (DCs) to be attracted to the tumor bed, where they engulf tumor cells. Then, mature DCs present antigens to tumor-specific cytotoxic T lymphocytes (CTLs), which ultimately results in CTLs killing the tumor cells [10].
Bladder cancer (BC) represents over 90% of all urothelial cancers, and with about 550,000 recognized new cases per year, is one of the top 10 most prevalent cancer in the world. It accounts for about three percent of all new cancer diagnoses and, with more than 200,000 deaths per year, is the 13th main reason for cancer death [11][12]. Men have a higher (9.6 per 100,000) global age-standardized incidence rate (ASR) than women (2.4 per 100,000). The prevalence of bladder cancer differs greatly by region. In the US and Europe, the incidence of BC is approximately 15 cases per 100,000 people per year [12][13]. Male sex, tobacco smoking, chemical exposure and family history are the main risk factors for this cancer [13]. The 5-year overall survival (OS) rate for BC is about 77%. Although, after five years following diagnosis, just 6% of individuals with metastatic BC are still alive. [14]. Due to the long-term survival rate and the use of intensive surveillance, BC has the highest lifetime cost for each patient of all cancer types [15].
Muscle-invasive bladder cancer (MIBC) and non-muscle invasive bladder cancer (NMIBC) are different types of bladder cancer [11]. NMIBC accounts for 80% of bladder cancer diagnoses and is found to carry mutations in the DNA helicase ERCC2, tumor suppressor TP53, and fibroblast growth factor receptor 3 (FGFR3) [16]. MIBC comprises about 20% of bladder cancer cases and is known to have mutations in tumor suppressor TP53, FGFR3, transcriptional activator ELF3, histone demethylase KDM6A, tumor suppressor RB1, and DNA helicase ERCC2 [11]. NMIBC is typically detected locally in the urothelium (stage Ta) or lamina propria (stage T1), whereas MIBC is more advanced with its invasion to the muscle (stage T2) or beyond (stages T3 and T4) [11][16]. In addition to surgery, patients with BC may receive radiotherapy, chemotherapy such as Mitomycin C, Adriamycin, Epirubicin, Platinum-based agents, Gemcitabine, and Doxorubicin or Bacillus Calmette–Guerin (BCG) immunotherapy. However, these treatment results remain poor [17][18]. In recent years, five immune checkpoint inhibitors (ICIs) including atezolizumab, pembrolizumab, durvalumab, nivolumab, and avelumab, have been approved by the European Medicines Agency (EMA) and US Food and Drug Administration (FDA) to treat metastatic and advanced bladder cancer, and have shown striking results [19].

2. Oncolytic Viruses

Viruses are known to cause cell death while creating an immune response against the infected cell; this response is by definition an ICD [20]. Different viruses have been studied in recent years as “oncolytic viruses” due to their ICD potential. Some of these viruses naturally induce ICD and some were genetically modified (recombinant form) to enhance their ICD potential or make them target cancerous cells specifically or enhance their immune stimulation potential. Oseledchyk et al. [21] investigated the Newcastle disease Virus (NDV) in its original form because this paramyxovirus has a natural tendency towards human cancer cells. They observed increased immune cell infiltration plus improved response to Immune Checkpoint Inhibitors (ICI). The virus caused apoptosis and its ICD effect was independent of lysis.
Liljenfeldt et al. [22] used a recombinant form of adenovirus that induced the expression of CD40 ligand on its host cells (called RAd-CD40L). The virus in combination with chemotherapeutic agent 5-fluorouracil induced enhanced systemic immunity, tumor shrinkage and survival in mice. The same recombinant adenovirus (called AdCD40L) was tested in a phase I/IIa clinical trial on eight patients with bladder cancer [23]. Post-treatment biopsy of those patients showed T cell infiltration, increased IFN-γ marker and reduced load of malignant cells; however, they did not have any controls. Circulatory T regulatory cells were also reduced in all of their patients.
Pseudovirion: Hojeij et al. [24] produced a modified human papillomavirus (HPV) that did not have the ability to replicate; hence the term pseudovirion. The pseudovirion was used to transfer a “suicide gene” into cancer cells. The suicide gene was herpes simplex virus thymidine kinase due to its ability to turn ganciclovir into its toxic form. Ganciclovir is a medication that is activated only in cells that contain thymidine kinase and causes cell death [25]. Hojeij et al. [24] observed that this combination induced ICD in vitro, reduced in vivo tumor growth and increased mice survival.
Lichtenegger et al. [26] studied a recombinant adenovirus that specifically replicates in cancer cells because these cells have nuclear localization of YB-1. YB-1 is a human oncogenic transcription factor and in this study was shown to be highly expressed in multiple bladder cancer cell lines. They showed ICD induced by this recombinant virus through release of HMGB1 and HSP70 in higher levels than the wild type virus and the control. The virus had a higher ICD induction capacity than doxorubicin, which is a known ICD-inducing chemotherapeutic drug.
Vesicular stomatitis virus containing both human and mouse GM-CSF were both tested in vitro by Rangsitratkul et al. [27]. In vitro they were able to induce ICD by release of HMGB1 and ATP plus expression of calreticulin. In vivo, the virus enhanced immune cell activation, tumor immune cell infiltration, and improved survival.
Annels et al. [28] studied Coxsackievirus A21 with the natural ability to target intracellular adhesion molecule-1 (ICAM-1). They discovered that the virus must be alive for its in vitro oncolytic effect and had varying oncolytic potency in different bladder cancer cell lines. The variation in oncolytic potency was associated with inability of the virus to enter the cytoplasm of some of the resistant cell lines. Some resistant cell lines also had low surface ICAM-1 expression. Mitomycin C treatment of the cells increased ICAM-1 expression only in those cell lines that were already capable of expressing ICAM-1. Mitomycin C also increased the oncolytic effect of Coxsackievirus A21 by the induction of apoptosis. The virus alone enhanced ICD markers by ecto-calreticulin expression and HMGB1 release. In their mouse model, injecting the combination of tumor-virus lysate caused an anti-cancer vaccination effect. However, the tumor cell line that was injected in the mouse was already modified to increase ICAM-1 production. In short, they saw oncolytic ability of the virus only in tumors that produce ICAM-1, using living virus, and MMC only enhanced oncolytic ability of the virus on cell lines that were already susceptible. In their mouse model, only CD4+ cells were shown to modulate AVE, as mice depleted with CD4+ were unable to respond with AVE while CD8+ and NK-depleted mice had intact responses. The same authors later tested this virus in a phase I clinical trial on patients with NMIBC [29]. They intravesically introduced the virus to 16 patients before their scheduled TURs; some patients also received low dose MMC in one of the instillations to enhance the oncolytic effect of the virus. Study of the resected tumors showed that the virus selectively replicated in the tumor cells. The patients’ urinary HMGB1 showed escalating levels following treatment, indicating the potential of this therapy to induce ICD only in cancerous cells. Up-regulation of immune checkpoint inhibitors PD-L1 and LAG3 and increased numerous cytokine production were also observed.

3. Anticancer Vaccination Effect

If an agent generates immunogenicity against cancer, its indirect anti-cancer effects are expected to remain in the immune system’s memory. Injection of such agents inside the tumor in mice has been shown to cause anti-tumor activity that extends beyond the injection site; i.e., distant tumors or tumors that are injected later are affected as well. Rejection of tumor cells in animal models after their immune system is exposed to cancerous cell compounds is called the anti-cancer vaccination effect (AVE).
Oseledchyk et al. [21] created two subcutaneous tumors in each mouse and injected their therapy agent (oncolytic virus NDV) locally inside only one of the tumors. They observed immune cell infiltration in the uninjected tumor as well as the injected tumor. This distant response could be due to traveling activated immune cells. A shift of inhibitory T cells to the effector phenotype was observed in their study, which is usually due to DC maturation [30]. The distant response can also be because their therapeutic agent is a replicating virus that can spread in the body and infect both tumors.
Garg et al. [31] investigated the role of ICD in generating AVE by studying rat cancer cell lines that are naturally resistant to AVE (AY27), and compared it to the murine cell line CT26 without this resistance. First, they induced apoptosis using the ICD-inducing agents Hypericin-photodynamic (Hyp-PDT) or mitoxantrone (MTX), then they injected the dying cells to one flank of the mouse or rat. The same animal was then challenged with live tumor cell on the other flank. They observed no AVE in rats injected with the AY27 cell line. They further showed that this was due to defective ICD in this cell line from failure to expose CRT on their surface.
Oresta et al. [32] observed AVE from high-dose-short-exposure of MMC. BC cells treated with a high dose of this chemotherapeutic agent for one hour underwent apoptosis enough to stimulate a lasting immune response in the mice that received them, and subsequently generated AVE. Previous studies that used low doses of the drug failed to show its ICD activity in short exposure times. Their study concluded that ICD generated from MMC relied on a cascade of events originating in cancer cell metabolism: oxidative phosphorylation causing increased mitochondrial permeability, followed by cytoplasmic release of mitochondrial DNA, and subsequent activation of inflammasome leading to IL-1 β secretion and eventually maturing dendritic cells.

4. Photodynamic Therapy (PDT)

PDT is a combination of three agents: photosensitizer, light, and oxygen. Together these three agents increase reactive oxygen species, causing cell apoptosis or necrosis [33]. Gerg et al. [34] used hypericin as their photosensitizer, an agent that disrupts normal endoplasmic reactions if activated by light. The study showed ICD induction through reactive oxygen species (ROS) production in the endoplasmic reticulum (ER stress) of human and mice bladder cancer cell lines. ICD in this study was shown by expression of surface calreticulin and active ATP release before apoptosis, subsequently leading to DC maturation and activation. The same authors later showed that autophagy regulates this response and reduces ICD (contrary to the Xu et al. [35] study). Attenuating autophagy in the second study enhanced immunogenicity of the cells; the authors postulated that autophagy protects cancer cells from ICD [36].

5. Inhibitory DAMPs (iDAMPs)

This type of damage-associated molecular pattern is shown to reverse the effect of DAMPs by reducing the immunogenicity of the cell death [37]. Nikolos et al. [38] showed that inhibition of prostaglandin-E2, a known iDAMP, increases ICD and turns chemo-immunotherapy unresponsive tumors into T-cell inflamed responsive tumors. The same authors previously showed concomitant release of iDAMP and DAMP as a mechanism of ICD resistance and failure of AVE generation when gemcitabine was added to chemotherapy regimen [39].

6. Radiotherapy, Chemotherapy and Combination Therapy

Radiotherapy is a known inducer of ICD [40]. Zeng et al. [41] showed that radiating the human bladder cancer cell line BT-B increases apoptosis and cell surface expression of calreticulin, HMGB1 and HSP70. The supernatant of irradiated bladder cell culture was capable of maturing a DC culture.
Combination of chemo and radiotherapy on top of checkpoint inhibitor therapy was shown to enhance patient response to treatment by Fukushima et al. [42]. They further tested this theory on mouse models and observed better survival of the mice with orthotropic bladder cancers if treated with all three therapies. They also showed that this was due to enhanced ICD.
In a clinical trial, Galsky et al. [43] attempted to enhance survival of metastatic urothelial cancer patient by combining gemcitabine, cisplatin, and ICI agent ipilimumab, through enhancing ICD generation in the treatment. The trial showed a high risk of grade 3 and above adverse events (81%) and the median overall survival of the patients was 13.9 months. The patients’ serum level of HMGB1 did not increase following this treatment. Some patients had increased CD4+ in their circulation, which correlated with better survival.

7. New Therapeutic Agents

Norcantharidin is a demethylated analog of cantharidin and has been used to treat cancer in China since 1984. Xu et al. [35] tested this drug’s ability to induce ICD in an acidic environment because some medications lose their potency at low pH. They concluded that this drug increased surface calreticulin and is capable of inducing DC maturation even in an acidic environment. The drug was also able to increase T cell infiltration of mouse tumors and prolong their survival. Unlike the study by Gerg et al. [34], this study showed that autophagy mediated ICD by showing that inhibiting autophagy blocked calreticulin exposure and DC maturation.
Docosahexaenoic acid (DHA) is a dietary polyunsaturated fatty acid with anticancer potential. Molinari et al. [44] observed surface exposure of calreticulin on bladder cancer cell lines after treating the cells with DHA.
Capsaicin, the spicy component of chili pepper, is a known apoptosis inducer in cancerous cells [45]. D’Eliseo et al. [46] showed this molecule’s ability to induce ICD in apoptotic human bladder cancer cell lines by increasing surface calreticulin, HSP90, and HSP70 plus ATP release. The same authors [47] later showed that capsaicin induced apoptosis and maturation of neighbor ingDCs. DC maturation was blocked by silencing CD91, which is considered a DAMP receptor.

This entry is adapted from the peer-reviewed paper 10.3390/curroncol29090526

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